The present invention relates to aligning the probe tips of a precision automated liquid handler.
In pharmaceutical, genomic and proteomic research and drug development laboratories, and other biotechnology applications, automated liquid handlers are used for handling laboratory samples in a variety of laboratory procedures. For example, liquid handlers are used for biotechnological and pharmaceutical liquid assay procedures, sample preparation, compound distribution, microarray manufacturing and the like. An automated liquid handler has a work bed that supports an array of sample receptacles. One-piece sample containing plates having an integral array of many sample containing receptacles or wells are widely used. The liquid handler has an array of multiple probes that are moved into alignment with one or more sample containing wells to carry out liquid handling operations such as adding liquid to the wells.
It is desirable to decrease the volumes of samples treated with automated liquid handlers. Sample containing plates with a footprint of about three and one-half by five inches and having an X-Y array of 96 wells in an eight by twelve well pattern have been widely used. In order to increase throughput and to reduce consumption of sample constituents, these plates are being superceded by microplates of the same footprint but having an array of smaller wells, for example 384 wells in a sixteen by twenty-four array. This trend is continuing, and there is a need for an automated liquid handler able to accommodate microtiter plates having a very dense array of a very large number of very small volume wells with volumes in the nanoliter range. High density microplates presently in use, with the same footprint as previously used plates, have 1,536 wells in a thirty-two by forty-eight well array.
Microtiter plates with a dense array of small, closely spaced wells present serious problems for an automated liquid handler. In operation, the handler must be precise enough to place every probe of a multiple probe array into alignment with a corresponding number of sample containing wells. As well size and spacing decreases, it becomes more difficult for an automated handler to reliably place the liquid handling probes directly over selected sample containing wells.
The margin for error in positioning the probes relative to the plates and wells decreases as well array density increases. One aspect of the problem is the precise location and alignment of the probe tips. If the group of probes is misaligned, or if individual probes of the group are out of position relative to other probes of the group, then it may not be possible to locate each probe of the group directly over a sample well of the plate. It is time consuming and difficult manually to check and reposition the probes to be sure they are properly positioned and aligned. Even if the probes are initially set up correctly, they can become displaced from their intended positions after a period of use. It would be desirable to provide an automated system for quickly and accurately checking and correcting probe tip positioning and alignment without substantial operator time and skill.
A principal object of the present invention is to provide an improved method for aligning probe tips of a precision liquid handler. Other objects are to provide a probe tip locating method using an electrical sensing capability that may preexist in the liquid handler; to provide a probe tip alignment method for detecting skew of a multiple probe array; to provide a probe tip alignment method for detecting misaligned probes and for bending a misaligned probe into an aligned position; to provide a probe tip alignment method that detects locator bed skew; to provide a probe tip alignment method that determines a center of probe scatter for use as a correction factor for a probe drive system; and to provide a probe tip alignment method that is automated and does not require operator time and skill.
In brief, in accordance with the invention, there is provided a probe tip alignment method for a precision liquid handler having a probe array moved by a probe drive system relative to a locator bed holding sample wells. The method includes sequentially inserting the probe tips of the probe array with the probe drive system into a locator well at a known position on the locator bed, then sequentially sensing the position of each probe tip in the locator well, and then mapping the positions of the probe tips.